title: Acetylation of the cell-fate factor dachshund determines p53 binding and signaling modules in breast cancer.
abstract: Breast cancer is a leading form of cancer in the world. The Drosophila Dac gene was cloned as an inhibitor of the hyperactive epidermal growth factor (EGFR), ellipse. Herein, endogenous DACH1 co-localized with p53 in a nuclear, extranucleolar compartment and bound to p53 in human breast cancer cell lines, p53 and DACH1 bound common genes in Chip-Seq. Full inhibition of breast cancer contact-independent growth by DACH1 required p53. The p53 breast cancer mutants R248Q and R273H, evaded DACH1 binding. DACH1 phosphorylation at serine residue (S439) inhibited p53 binding and phosphorylation at p53 amino-terminal sites (S15, S20) enhanced DACH1 binding. DACH1 binding to p53 was inhibited by NAD-dependent deacetylation via DACH1 K628. DACH1 repressed p21CIP1 and induced RAD51, an association found in basal breast cancer. DACH1 inhibits breast cancer cellular growth in an NAD and p53-dependent manner through direct protein-protein association.
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.forename: Kongming
authors.initials: K
authors.lastname: Wu
authors.forename: Michael
authors.initials: M
authors.lastname: Gormley
authors.forename: Adam
authors.initials: A
authors.lastname: Ertel
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.forename: Gabriele
authors.initials: G
authors.lastname: Disante
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Li
authors.forename: Hallgeir
authors.initials: H
authors.lastname: Rui
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Quong
authors.forename: Steven B
authors.initials: SB
authors.lastname: McMahon
authors.forename: Haiteng
authors.initials: H
authors.lastname: Deng
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin; C486747:DACH1 protein, human; D005136:Eye Proteins; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53